Design, synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease

Yifan Zhao; Feng Ye; Jian Xu; Qinghong Liao; Lei Chen; Weijia Zhang; Haopeng Sun; Wenyuan Liu; Feng Feng; Wei Qu

doi:10.1016/j.bmc.2018.06.018

Design, synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease

Bioorg Med Chem. 2018 Jul 30;26(13):3812-3824. doi: 10.1016/j.bmc.2018.06.018. Epub 2018 Jun 14.

Authors

Yifan Zhao¹, Feng Ye¹, Jian Xu¹, Qinghong Liao¹, Lei Chen², Weijia Zhang¹, Haopeng Sun³, Wenyuan Liu², Feng Feng⁴, Wei Qu⁵

Affiliations

¹ School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
² Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
⁴ School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Food and Pharmaceutical Science College, Huaian 223003, China. Electronic address: fengfeng@cpu.edu.cn.
⁵ School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 210009, China. Electronic address: popoqzh@126.com.

PMID: 29960728
DOI: 10.1016/j.bmc.2018.06.018

Abstract

To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC₅₀ = 1.7 and 2.7 μM, respectively), Aβ_1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ_1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25 μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H₂O₂, okadaic acid (OA) and Aβ_1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.

Keywords: Alzheimer's disease; Aβ(1-42) aggregation inhibitory; Bivalent β-carbolines; Neuroprotective activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Binding Sites
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Carbolines / chemistry*
Carbolines / metabolism
Carbolines / pharmacology
Cell Line, Tumor
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / metabolism
Cholinesterase Inhibitors / pharmacology
Drug Design*
Humans
Hydrogen Peroxide / toxicity
Inhibitory Concentration 50
Molecular Docking Simulation
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / pharmacology
Okadaic Acid / toxicity
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Carbolines
Cholinesterase Inhibitors
Neuroprotective Agents
Peptide Fragments
amyloid beta-protein (1-42)
Okadaic Acid
Hydrogen Peroxide
Acetylcholinesterase
Butyrylcholinesterase